PROJECT SUMMARY The cognitive aging field has long debated whether presymptomatic brain disease accounts for a proportion of what is considered to be normal age-related cognitive decline. This is most notable in relation to Alzheimer's disease (AD) not only because it is a highly prevalent age-associated condition, but also because several features of AD are seen in normal aging. In particular, decline in episodic memory, deposition of - amyloid plaques, and neurofibrillary tangle-related hippocampal atrophy are all aspects of AD that are also common in cognitively intact older people. However, the effects of AD pathology are not straightforward and are likely to be mediated by intervening factors that can be characterized as vulnerability and reserve. Within the past several years, scientific advances have allowed the measurement of the multiple processes that may be involved in this model of age-related memory loss. Thus, it is possible to measure -amyloid with positron emission tomography (PET) and the amyloid imaging agent [11C] Pittsburgh Compound B (PIB), to assess neurofibrillary tangle burden and hippocampal atrophy with magnetic resonance imaging (MRI), and to assess reserve processes with PET measures of glucose metabolism (using [18F]-Flurodeoxyglucose, or FDG) and with functional MRI (fMRI). In this project, a group of 125 older cognitively intact individuals will be recruited over 5 years, carefully characterized in terms of overall cognition and episodic memory, and studied with PIB- and FDG-PET imaging and structural MRI. A subgroup of 50 of these subjects, along with 50 healthy young subjects will be studied with fMRI and an event-related behavioral paradigm that contrasts brain activity during successfully remembered and forgotten items. A major question is whether, and how, older people without evidence of - amyloid deposition or hippocampal atrophy differ from older people with these characteristics, and from younger people. In addition key hypotheses will be tested in continuous multivariate models in which PET measures of -amyloid and MR measures of hippocampal atrophy are expected to be related to poorer episodic memory function, while resting prefrontal glucose metabolism will attenuate this relationship. Similar findings are expected during cognitive activity using fMRI, in which diminished brain activity in the medial temporal lobes may be related to -amyloid deposition, and better performance may be related to increased prefrontal cortical activation. Finally, a subgroup of subjects will be re-evaluated at a 2-year interval to see whether these measures predict change over time in cognition. In total, this project will both provide a description of optimal cognitive aging independent of brain amyloid deposition, and will begin to unravel the mechanisms associated with the loss and preservation of memory function in aging.